In recent years, it has been revealed that various stem cells contribute towards the repairing process of damaged tissues, and development of novel regenerative medicines that induce functional tissue regeneration by mobilizing a large number of stem cells to lesion sites is in progress. To bring these novel regenerative medicines to realization, (i) stem cells that are mobilizable to lesion sites must be present abundantly in vivo; and (ii) factors that mobilize stem cells to lesion sites must be isolated/identified.
Examples of stem cells that are mobilizable to lesion sites include tissue stem cells present in lesion areas or nearby tissues, and bone marrow-derived stem cells present in peripheral blood. In recent years, it has been reported that bone marrow-derived cells contribute to many types of damaged tissue regenerations, but the mechanism for mobilizing bone marrow-derived cells to lesion sites is unknown. Bone marrow-derived cells as used herein are distinguished from hematopoietic stem cells which have the potential to differentiate into blood cells (leukocytes and erythrocytes), and include stem cells represented by cells called bone marrow mesenchymal stem cells, or tissue progenitor cell groups present in the bone marrow. Bone marrow mesenchymal stem cells are undifferentiated stem cells with the potential to differentiate into osteoblasts, adipocytes, and chondrocytes, and can further differentiate into other mesenchymal cells such as fibroblasts, muscle cells, stromal cells, and tendon cells. Recently, it has been proved that bone marrow mesenchymal stem cells differentiate into nerve cells and further to epithelial cells (such as skin keratinocytes) and vascular endothelial cells (Non-patent Document 9). Tissue progenitor cells are defined as undifferentiated cells having a unidirectional potential to differentiate into specific tissues/cells other than those of the blood system, and include undifferentiated cells with the potential to differentiate into mesenchymal tissue, epithelial tissue, nerve tissue, parenchymatous organs, and vascular endothelium, as mentioned above.
HMGB1 (High Mobility Group Box 1: High mobility group 1 protein) is a protein with molecular weight of about 25,000 that exists in almost all types of cells in vivo. According to previous reports, the following functions are known:    1) HMGB1 regulates gene expression by intracellularly binding with DNA to control chromatin structure (Non-patent Document 1);    2) HMGB1 is secreted from monocytes or macrophages present in inflammatory tissues by the action of inflammatory cytokines TNF-α, IL-1, and LPS, and extracellularly binds to RAGE (Receptor for Advanced Glycation End products) (Non-patent Document 2) to induce strong inflammatory reactions (Non-patent Document 3);    3) HMGB1 is released from hypoperfusion-induced necrosed cells into surrounding tissues (Non-patent Document 4);    4) HMGB1 is associated with the progression of inflammation in patients with septicemia, a severe infectious disease (Non-patent Document 5);    5) administration of HMGB1 to infarcted areas in a myocardial infarction model promotes the division/proliferation of stem cells present in the myocardium, and therefore the regeneration/functional recovery of the myocardium (Patent Document 1);    6) administration of HMGB1 to a model animal with hypoperfusive liver failure prior to the induction of hypoperfusive conditions alleviates the degree of hepatic impairment (Non-patent Document 6);    7) administration of HMGB1 to lesion sites in a muscle injury model directs simultaneously-administered vascular progenitor cells to lesion sites, and therefore promotes muscular tissue regeneration (Non-patent Document 7); and    8) HMGB1 induces neurite formation in nerve cells (Non-patent Document 8). However, no previous reports showed that bone marrow-derived stem cells, in particular those mesenchymal stem cells that can differentiate into osteoblasts, chondrocytes, adipocytes, and the like, are mobilized to damaged tissues.
Conventionally it was thought that central nerve cells in the brain and spinal cord cannot be regenerated once damaged. However, recently the existence of neural stem cells became known and induction of these cells was made possible. The neural stem cell niche within the nominal nerve system has also been identified. Therefore, recovery of damaged central neurons, which was long considered impossible, is now expected to be feasible. Currently, research related to neuronal regeneration for brain and spinal cord injury, degenerative diseases, and the like is being expanded.
The main causes of brain tissue (cells) injury are traumatic cerebral contusion and cerebral ischemic diseases. Other causes can be injury resulting from brain surgeries such as brain tumor removal. In particular, complete removal of neuroglioma that have developed from cerebral parenchymal cells is difficult, and there is no choice but to stop at partial removal to avoid damage to motor and language functions. Moreover, malignant neuroglioma has a worse prognosis, and none of the treatments of active research in recent years ranging from chemotherapy and radiotherapy to immunotherapy/gene therapy has achieved satisfactory effects. Accordingly, an ideal treatment would be one that can remove as many tumor cells as possible, and restore damage to cerebral functions that results from the removal.